Submissions for variant NM_001317778.2(SFTPC):c.176A>G (p.His59Arg)

gnomAD frequency: 0.00010  dbSNP: rs201567623

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000366166	SCV000473003	likely benign	Interstitial lung disease 2	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000271807	SCV000473004	likely benign	Surfactant metabolism dysfunction, pulmonary, 2	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Mendelics	RCV002248629	SCV002520006	benign	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002402077	SCV002713403	uncertain significance	Hereditary pulmonary alveolar proteinosis	2019-08-02	criteria provided, single submitter	clinical testing	The p.H59R variant (also known as c.176A>G), located in coding exon 2 of the SFTPC gene, results from an A to G substitution at nucleotide position 176. The histidine at codon 59 is replaced by arginine, an amino acid with highly similar properties. In one study, this variant was detected in trans with a second SFTPC alteration in a female with onset of symptoms at birth (Willander H et al. Proc. Natl. Acad. Sci. U.S.A., 2012 Feb;109:2325-9). In addition, this variant was identified in an individual with combined pulmonary fibrosis and emphysema syndrome with onset of symptoms at age 11 years; this individual's healthy father was also heterozygous for the variant (Kröner C et al. Eur. Respir. J., 2015 Jul;46:197-206). In our internal cohort, this variant was observed in the homozygous state in a proband exhibiting surfactant deficiency on lung biopsy; parental testing revealed that both of the unaffected parents were heterozygous. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003556368	SCV004278155	uncertain significance	not provided	2022-11-23	criteria provided, single submitter	clinical testing	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. 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 362554). This missense change has been observed in individual(s) with clinical features of SFTPC-related conditions (PMID: 25657025, 33526882). This variant is present in population databases (rs201567623, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 59 of the SFTPC protein (p.His59Arg).
Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center	RCV002509375	SCV002547377	likely risk allele	Pulmonary fibrosis	2022-06-09	no assertion criteria provided	research