Submissions for variant NM_001378454.1(ALMS1):c.1609C>G (p.Leu537Val)

gnomAD frequency: 0.00041  dbSNP: rs202111717

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000476920	SCV000541360	uncertain significance	Alstrom syndrome	2022-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 538 of the ALMS1 protein (p.Leu538Val). This variant is present in population databases (rs202111717, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with ALMS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 403950). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Not Available"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000732324	SCV000582649	uncertain significance	not provided	2024-09-09	criteria provided, single submitter	clinical testing	Reported in a patient with Bardet-Biedl syndrome who harbored a second variant in trans (PMID: 34716235); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 37541188, 34716235)
Eurofins Ntd Llc (ga)	RCV000732324	SCV000860266	uncertain significance	not provided	2018-04-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000476920	SCV000897041	uncertain significance	Alstrom syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV001172510	SCV001335563	likely benign	Monogenic diabetes	2018-01-12	criteria provided, single submitter	research	ACMG criteria: BP4 (6 predictors), BP1 (missense when truncating are causative)=likely benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001358710	SCV001554535	uncertain significance	not specified	2023-10-30	criteria provided, single submitter	clinical testing	Variant summary: ALMS1 c.1606C>G (p.Leu536Val) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00033 in 249302 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ALMS1 causing Alstrom Syndrome With Dilated Cardiomyopathy (0.00033 vs 0.0018), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1606C>G in individuals affected with Alstrom Syndrome With Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002393077	SCV002703153	likely benign	Cardiovascular phenotype	2022-03-14	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV000476920	SCV003928157	uncertain significance	Alstrom syndrome		criteria provided, single submitter	research	Potent mutations in ALMS1 are associated with a rare condition called Alstrom syndrome. It can cause excessive eating, insulin resistance. However, no evidence is found to ascertain the role of rs202111717 in Alstrom syndrome yet.
CeGaT Center for Human Genetics Tuebingen	RCV000732324	SCV004154983	likely benign	not provided	2022-05-01	criteria provided, single submitter	clinical testing	ALMS1: BP4
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004816673	SCV005071468	uncertain significance	Retinal dystrophy	2022-01-01	criteria provided, single submitter	clinical testing