Submissions for variant NM_000183.3(HADHB):c.589T>C (p.Ser197Pro)

gnomAD frequency: 0.00002  dbSNP: rs142475516

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000519204	SCV000619525	uncertain significance	not provided	2020-02-14	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV001044239	SCV001208026	uncertain significance	Mitochondrial trifunctional protein deficiency	2022-02-10	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 197 of the HADHB protein (p.Ser197Pro). This variant is present in population databases (rs142475516, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with HADHB-related conditions. ClinVar contains an entry for this variant (Variation ID: 450898). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Illumina Laboratory Services, Illumina	RCV001044239	SCV001301630	uncertain significance	Mitochondrial trifunctional protein deficiency	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Mayo Clinic Laboratories, Mayo Clinic	RCV000519204	SCV001713162	uncertain significance	not provided	2020-05-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003258848	SCV003945230	uncertain significance	Inborn genetic diseases	2023-04-05	criteria provided, single submitter	clinical testing	The c.589T>C (p.S197P) alteration is located in exon 8 (coding exon 7) of the HADHB gene. This alteration results from a T to C substitution at nucleotide position 589, causing the serine (S) at amino acid position 197 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV000519204	SCV004183724	uncertain significance	not provided	2023-11-01	criteria provided, single submitter	clinical testing	HADHB: PM2, PP4